As to neurotrophic factors, a number of factors have been discovered, since nerve growth factor (NGF) was discovered by Levi-Monntalcini, Anu. N. Y. Acad. Sci., 55, 330 (1952) and Cohen et al., Proc. Natl. Acad. Sci. USA, 40, 1014 (1954). These factors have been considered to bring a variety of functions such as differentiation, maturation, survival, maintenance of functions and proliferation. These factors include brain-derived neurotrophic factor (BDNF) [Y. A. Barde et al., EMBO J., 1, 549-553 (1982)] and ciliary neurotrophic factor (CNTF) [D. Watters et al., J. Neurochem., 49, 705-713 (1987)] as well as NGF mentioned above.
Human nerve growth factor 2 (NGF-2) is disclosed as polypeptide (I) in European Patent Publication No. 386,752, and published in FEBS Letters, 266, 187-191 (1990). The same factor is reported as NT-3 in documents such as Hohn et al., Nature, 344, 399 (1990), and disclosed in PCT International Publication No. W091/03569.
In this specification, human nerve growth factor-2 is sometimes also briefly referred to as human NGF-2/NT-3. With respect to human NGF-2/NT-3, (1) human NGF-2/NT-3 gene is strongly expressed in the kidney and in the hippocampus and the cerebellum in the brain, (2) the gene is expressed more strongly in the neonates than in the mature animals, and (3) the gene acts on nerve cells such as nodose ganglion-derived nerve cells on which NGF or BDNF does not act or weakly acts. From these facts, it is conceivable that NGF-2/NT-3 importantly acts upon development of nerve systems.
In differentiation of the blood cells, pluripotent stem cells are first differentiated into lymphatic stem cells and myeloid stem cells. Next, the lymphatic stem cells are differentiated into T lymphocytes and plasma cells through several differentiation stages. The myeloid stem cells are differentiated into the basocytes, acidocytes, monocytes and macrophages, neutrophils, megakaryocytes and erythrocytes. It has been known that a number of hematopoietic factors such as colony stimulating factors and interleukins are concerned in the respective differentiation stages, and some of these factors are known to be clinically useful.
The hematopoietic factors such as various colony stimulating factors and interleukins are factors acting in the differentiation stages of the blood cells, and very few act on the blood cells in the final differentiation stage of the peripheral blood, for example, basocytes, acidocytes, monocytes and neutrophils, to allow their proliferation. NGF is known to stimulate colony formation in the peripheral blood [Proc. Natl. Acad. Sci., 85, 6508 (1988)].